OsteoGeneX is developing a therapeutic directed against the new bone target Sclerostin (SOST) for the treatment of osteoporosis and related bone disorders. Through genomic approaches Sclerostin was identified as a master regulator of bone mass affecting men and women. Using proteomic approaches Dr. Ellies & Krumlauf discovered and patented Sclerostin's mechanism of action. Since then, Dr. Ellies was awarded an NIH Phase I SBIR "proof of concept" grant to screen for compounds that would block SOST function. This library was hand picked by Dr. Gunda Georg, University Distinguished Professor of Medicinal Chemistry, University of Kansas. The NIH has identified Dr. Georg as one of the top 5 percent of researchers receiving funding from the NIH for her work in medicinal chemistry and drug development and discovery. Dr. Ellies has identified many lead candidates that work to block SOST. These candidates need to be authenticated using a novel biochemical approach looking specifically at the binding of SOST to its receptor - LRP5. The binding of these proteins is what regulates new bone formation. Recent news about bone building therapeutics - PTH and analogs - having to carry a black box warning has created a need for a new bone building therapeutic. An alternative to PTH therapy is through the use of Sclerostin as an ideal anabolic target for drug development. The purpose of this SBIR Phase II application is to identify the most optimal dosing of a single or couple of authenticated lead candidates that will build new bone. To accomplish this end, we propose to carry out the following specific aims; authenticate positive lead candidates; calculate effective dosage and delivery; and analyze their effect in rat models for osteoporosis. PUBLIC HEALTH RELEVANCE: Osteoporosis is one of the most prevalent problems in our society. New drug targets for controlling bone deposition must be identified, as our understanding of the molecular control of bone deposition is poor. While there is no cure for osteoporosis, the FDA has approved the use of certain drugs to prevent and treat osteoporosis. These drugs, especially those directed against bone resorption, cause undesirable side effects and may not significantly reduce fracture risk in the target populations. Thus, there is a critical need to identify new and better therapeutics that would result in better patient outcomes. This proposal is aimed at authenticating novel drugs that increase bone deposition, rather than prevent resorption, to offset the bone loss of osteoporosis. Furthermore, this proposal will establish a dosage regime & delivery, and show proof of concept in animals. [unreadable] [unreadable] [unreadable]